Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells

Okada, Masahiro; Chikuma, Shunsuke; Kondo, Taisuke; Hibino, Sana; Machiyama, Hiroaki; Yokosuka, Tadashi; Nakano, Miyako; Yoshimura, Akihiko

doi:10.1016/j.celrep.2017.07.027

Cited by 172 publications

(151 citation statements)

References 68 publications

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“…In the cancer microenvironment, blocking core‐fucosylation induces a T cell response. In contrast, in colitis and systemic lupus erythematosus increased core‐fucosylation is accompanied by an increased T cell activation and response . However, in both cases, core‐fucosylation inactivation may be a potential new therapeutic avenue.…”

Section: Discussionmentioning

confidence: 99%

CDG and immune response: From bedside to bench and back

Pascoal

Francisco

Ferro

et al. 2019

J of Inher Metab Disea

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Glycosylation is an essential biological process that adds structural and functional diversity to cells and molecules, participating in physiological processes such as immunity. The immune response is driven and modulated by protein‐attached glycans that mediate cell‐cell interactions, pathogen recognition and cell activation. Therefore, abnormal glycosylation can be associated with deranged immune responses. Within human diseases presenting immunological defects are congenital disorders of glycosylation (CDG), a family of around 130 rare and complex genetic diseases. In this review, we have identified 23 CDG with immunological involvement, characterized by an increased propensity to—often life‐threatening—infection. Inflammatory and autoimmune complications were found in 7 CDG types. CDG natural history(ies) and the mechanisms behind the immunological anomalies are still poorly understood. However, in some cases, alterations in pathogen recognition and intracellular signaling (eg, TGF‐β1, NFAT, and NF‐κB) have been suggested. Targeted therapies to restore immune defects are only available for PGM3‐CDG and SLC35C1‐CDG. Fostering research on glycoimmunology may elucidate the involved pathophysiological mechanisms and open new therapeutic avenues, thus improving CDG patients' quality of life.

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Section: Discussionmentioning

confidence: 99%

CDG and immune response: From bedside to bench and back

Pascoal

Francisco

Ferro

et al. 2019

J of Inher Metab Disea

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“…Spleen and lymph node cell suspensions were prepared from the indicated mice, and CD4 þ T cells were isolated using a mouse CD4 þ T Cell Isolation Kit and autoMACS Pro (Miltenyi Biotec). CD4 þ CD62L þ -na€ ve T cells were prepared as previously described (21). For preparation of CD4 þ CD25 þ Tregs, isolated CD4 þ T cells were stained with allophycocyanin (APC)-conjugated antimouse CD25 antibody, followed by positive selection with anti-APC microbeads using autoMACS.…”

Section: Mouse T-cell Isolationmentioning

confidence: 99%

Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance

et al. 2018

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Enhanced infiltration of regulatory T cells (Treg) into tumor tissue is detrimental to patients with cancer and is closely associated with poor prognosis as they create an immunosuppressive state that suppresses antitumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here, we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg genetic programs, contribute to Treg-mediated suppression of antitumor immunity in the tumor microenvironment. Mice lacking Nr4a1 and Nr4a2 genes specifically in Tregs showed resistance to tumor growth in transplantation models without exhibiting any severe systemic autoimmunity. The chemotherapeutic agent camptothecin and a common cyclooxygenase-2 inhibitor were found to inhibit transcriptional activity and induction of Nr4a factors, and they synergistically exerted antitumor effects. Genetic inactivation or pharmacologic inhibition of Nr4a factors unleashed effector activities of CD8 cytotoxic T cells and evoked potent antitumor immune responses. These findings demonstrate that inactivation of Nr4a in Tregs breaks immune tolerance toward cancer, and pharmacologic modulation of Nr4a activity may be a novel cancer treatment strategy targeting the immunosuppressive tumor microenvironment. This study reveals the role of Nr4a transcription factors in Treg-mediated tolerance to antitumor immunity, with possible therapeutic implications for developing effective anticancer therapies. .

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“…A modified molecule, similar to atezolizumab but with reduced core fucosylation, demonstrated increased binding to Fc-gamma-receptor-IIIa and enhanced ADCC against PD-L1-expressing tumor cells in a cell-line model [79]. Knockout of the fucosyltransferase gene FUT8 or the pharmacologic inhibition of this gene, which decreased fucosylation, resulted in decreased PD-1 expression and increased T-cell activation in mice, again supporting this as a potential mechanism to enhance the activity of checkpoint inhibitors [80]. Phase I trials of non-fucosylated ipilimumab are enrolling.…”

Section: Non-fucosylated Antibodiesmentioning

confidence: 74%

Structure and Optimization of Checkpoint Inhibitors

Picardo

Doi

Hansen

2019

Cancers

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With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors.

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Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells

Cited by 172 publications

References 68 publications

CDG and immune response: From bedside to bench and back

CDG and immune response: From bedside to bench and back

Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance

Structure and Optimization of Checkpoint Inhibitors

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